This renewal application seeks to extend our prospective evaluation of predictors of type 2 diabetes mellitus (DM) in the Nurses'Health Study, a large prospective cohort with archived blood specimens. Type 2 DM is a major and increasing public health problem, affecting at least 17 million Americans. Obesity is strongly associated with risk for type 2 DM, yet mechanisms whereby obesity causes type 2 DM are uncertain. Recent evidence implicates "adipokines", including leptin and its receptors, acylation-stimulating protein (ASP), resistin, and adiponectin, and free fatty acids (FFA), all secreted by adipose tissue, in the pathogenesis of type 2 DM. We propose to study 1) the role of plasma levels of these adipokines and FFA as predictors of incident Type 2 DM, and 2) the association of specific genetic variants important in regulating adipokine and FFA metabolic pathways, including leptin receptor, resistin, IL-6, fatty acid binding proteins 2 and 4 (FABP2, FABP4), CD36, and peroxisome proliferators-activated receptor gamma coactivator- 1 (PGC 1), with risk of type 2 DM. Genetic studies will target putative functional variants in gene coding regions, and will also investigate associations between ancestral haplotypes at each locus and type 2 DM risk. We will also examine specific gene-environment interactions (including the role of diet, exercise, and obesity itself) and risk of type 2 DM. Elucidation of interrelationships among adipokines, FFA, their genetic determinants, lifestyle risk factors, and development of type 2 DM may suggest new treatment and/or prevention strategies. Previous work in this cohort has contributed to clarifying the major roles of body fat and its distribution, physical activity level, dietary factors, and inflammation as determinants of type 2 DM. We seek to build on this body of work by conducting nested case-control analyses in an existing database that includes 121,700 U.S. female nurses aged 35-55 at baseline, with follow-up and documentation through 2004 of 1,275 incident cases of type 2 DM among the 32,825 women who provided a blood sample in 1989-90. The unique features of this established cohort study, including its prospective design, large size, long duration, high follow-up rates (exceeding 90 percent over 28 years), availability of stored blood specimens, and cost-efficiency, make this database an unparalleled resource in the etiologic study of type 2 DM in women.